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Research Article Copyright © All rights are reserved by Alexandru Caraba

Corrected QT Interval in Systemic Sclerosis Patients

Alexandru Caraba1*, Andreea Munteanu1, Flavia Corina Babalic1 and Mihaela Nicolin2
1
Department of Internal Medicine, Division of Rheumatology, Victor Babeș University of Medicine and Pharmacy, Romania
2
Department of Cardiology, Victor Popescu Emergency Clinical Military Hospital Timisoara, Romania

*Corresponding author: Alexandru Caraba, Department of Internal Medicine, Received Date: August 29, 2019
Division of Rheumatology, Victor Babeș University of Medicine and Pharmacy,
Timișoara, Romania. Published Date: September 09, 2019

Abstract
Introduction: Cardiac involvement in patients with systemic sclerosis represents an important cause of morbidity and mortality.
Electrocardiographic abnormal findings are identified in 25-75% of SSc patients, being considered an independent predictor of mortality. In SSc,
even without cardiac symptoms, QT and corrected QT (QTc) intervals appear prolonged, which can lead to life-threatening tachyarrhythmias. The
aim of this study was to assess the QTc interval in SSc patients, and, on the other hand, the correlations between QTc and nailfold capillary findings
in these patients.

Material and methods: This case control study was performed on a group of 22 patients with SSc, who fulfilled the 2013 ACR/EULAR
Classification Criteria for Systemic Sclerosis and 22 healthy subjects, matched for age and gender, as controls. In all the SSc patients and controls were
performed: 12-lead standard electrocardiographic recordings and nailfold capillaroscopy. QTc interval and nailfold capillaries density were recorded
in SSc patients and controls. In SSc were determined: antinuclear antibodies, anti-topoisomerase I, anti-centromere and anti-RNA polymerase III
antibodies, too. Data are presented as mean ± standard deviation. Statistical analyses were performed using the Student’s t-test, ANOVA test, and the
Pearson’s correlation. Differences were considered statistically significant at the value of p < 0.05.

Results: The values of QTc interval were prolonged in SSc group than in controls (p<0.01). These values of QTc interval increased with the
severity of the nailfold capillaroscopic pattern, the differences having statistical significance (p<0.001). It was demonstrated a statistically significant
negative correlation between the values of QTc intervals and nailfold capillaries density, this correlation being stronger with the increase of the
severity of nailfold capillaroscopic pattern.

Conclusion: SSc patients present prolonged QTc interval, even they are without any cardiac symptoms, requiring the ambulatory 24-hour ECG
monitoring in order to identify ventricular arrhythmias and initiate appropriate therapy.

Keywords: Corrected QT interval; Nailfold capillaroscopy; Systemic sclerosis

Introduction
used (clinical exam, electrocardiography, cardiac ultrasonography,
Systemic sclerosis (SSc) is a chronic disorder, characterized
cardiac magnetic resonance imaging) [4]. The rapid skin thickness
by autoimmunity, inflammation, functional and then structural
progression is associated with higher cardiac involvement. Cardiac
abnormalities of micro vessels and, finally, widespread interstitial
causes represent 20% to 36% of deaths associated with SSc. Several
and vascular fibrosis involving skin and internal organs [1].
mechanisms are involved in SSc heart disease: microvascular
Based on clinical features and the presence of specific SSc-related
alterations, myocardial inflammation, fibrosis and autonomic
autoantibodies, the following forms of SSc have been described:
dysfunction [1,2,5].
limited SSc (lcSSc), diffuse SSc (dcSSc) and SSc without skin
involvement [2]. Electrocardiographic abnormal findings are identified
in 25-75% of SSc patients, being represented by: atrial and
Cardiac involvement in SSc can be primary, direct consequence
ventricular tachyarrhythmias, conduction abnormalities and
of this disease or secondary, associated with SSc pulmonary
bradyarrhythmias. They are considered to be an independent
hypertension or renal crisis [3]. The clinical features of SSc heart
predictor of mortality [6]. In SSc, even without cardiac symptoms,
involvement are highly variable, from silent forms to heart failure.
QT and corrected QT (QTc) intervals appear prolonged, which can
Based on this fact, the prevalence of SSc cardiac involvement varies
lead to life-threatening tachyarrhythmias [7].
greatly, from 10% to 50%, depending on the diagnostic method

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 Archives of Rheumatology & Arthritis Research Volume 1-Issue 1

QT interval, measured from the beginning of the QRS complex
to the end of the T wave, represents the time required for all
ventricular depolarization and repolarization processes to occur.
It depends on many physiologic and pathologic factors, including
heart rate, which plays a major role. Several methods have been
used to correct the QT interval, all of which consider the heart rate,
generating corrected QT (QTc) [8].
the Pearson’s correlation. Differences were considered statistically
significant at the value of p<0.05.
Results
Baseline demographic data of SSc patients and controls are
presented in the Table 1.
Table 1: Demographic data in SSc patients and controls.

The aim of this study was to assess the QTc interval in SSc Parameter Value (Mean±Standard Deviation)
patients, and, on the other hand, the correlations between QTc and SSc Patients Controls
nailfold capillary findings in these patients. Sex[n(%)] 22 22
Males 6(27.27%) 6(27.27%)
Materials and Methods Females 16 (72.72 %) 16 (72.72 %)
Patients Mean age (years) 50±4.55 51.24±4.72

This case control study was performed on a group of 22 patients Mean length of SSc
5.36±3.18 -
evolution (years)
with SSc without cardiac symptoms and 22 healthy subjects,
Mean length
matched for age and gender, as controls. All patients fulfilled the
of Raynaud’s
2013 ACR/EULAR Classification Criteria for Systemic Sclerosis [9]. 8.36±3.68 -
phenomenon
Exclusion criteria were represented by: overlap syndromes, overt evolution (years)
cardiac diseases unrelated with SSc, tachyarrhythmias with heart Azathioprine
rate higher than 90 beats/minute, pre-existing branch blocks, The drugs used by (14 patients)
the SSc patients Cyclophosphamide
uncontrolled systemic hypertension, pulmonary hypertension, -
in the moment of (6 patients)
right ventricular dysfunction, diabetes mellitus, chronic kidney investigation Methotrexate (2
patients)
disease, current smokers, pregnancy or breastfeeding women,
treatment with drugs which prolonged QT interval. All the patients Among the SSc patients, 19 had diffuse cutaneous SSc,
gave their informed consent. The study was approved by the Ethics whereas 3 patients had the limited form of the disease. Raynaud’s
Committee of “Victor Babeș” University of Medicine and Pharmacy, phenomenon was present in all cases.
Timişoara, Romania. This study respects the Declaration of Helsinki.
Antinuclear antibodies were demonstrated in all patients.
Methods Anti-topoisomerase I antibodies were identified in 12 SSc patients,
12-lead standard electrocardiographic recordings (recording anti-RNA polymerase III antibodies in 7 SSc patients, whereas anti-
speed of 25mm/sec, voltage 10 mm/mV) using BTL-08 SD3 centromere antibodies in 3 patients.
equipment were performed in all patients and controls. QT interval The density of nailfold capillaries was reduced in SSc patients
was recorded in all patients and controls; then, using Bazzett’s than in controls (p<0.001). The values of QTc interval were
formula, QTc interval was determined. Normal values of QTc prolonged in SSc group than in controls, the difference being
interval were below 440 msec [8]. statistically significant (p<0.01) (Table 2).
The density of nailfold capillaries/mm was determined by Table 2: Parameters assessed in SSc patients and controls.
nailfold capillaroscopy (USB Digital Microscope, 2.0Mega Pixel Parameter SSc Patients Controls p
Digital Camera). Before this procedure, the patients and controls
QTc (msec) 455.31±44.60 420.68±19.75 < 0.01
took place in a room with a stable temperature of 20-22°C for at least
Capillaries
15 minutes, in order to avoid capillaries vasoconstriction, which can 8.06±2.45 11.54±1.04 < 0.001
density/mm
induce false positivity for avascular areas. The 2nd, 3rd, 4th and 5th
Table 3: QTc interval values in SSc patients.
fingers of both hands were examined. Giant capillaries, capillaries
hemorrhages, avascular areas, ramified/bushy capillaries, and p
Nailfold Capillaroscopic Pattern
capillary architecture were the recorded nailfold capillaroscopic Parameter
parameters. Patients with SSc may develop three capillaroscopic Early Active Late
patterns defined as: early, active, and late [10]. Nailfold capillaries Number of
6 9 7
density/mm was the parameter used in the statistical analysis. patients
Capillaries
Antinuclear antibodies, anti-topoisomerase, anti-centromere, density/ 10.85±0.56 8.42±0.94 5.18±1.34 < 0.001
and anti-RNA polymerase III antibodies were determined using mm
indirect immunofluorescence (HELMED). 411.83 ± 449.77± 499.71±
QTc (msec) < 0.001
18.46 21.06 43.01
Statistical analysis
Based on Cutolo’s capillaroscopic patterns [10], the studied SSc
Data are presented as mean±standard deviation. Statistical patients were classified as: early (6 patients), active (9 patients),
analyses were performed using the Student’s t-test, ANOVA test, and and late (7 patients) capillaroscopic patterns. The data analysis

Citation: Alexandru Caraba, Andreea Munteanu, Flavia Corina Babali, Mihaela Nicolin. Corrected QT Interval in Systemic Sclerosis Patients. Page 2 of 4
Arch Rheum & Arthritis Res. 1(1): 2019. ARAR.MS.ID.000501.
 Archives of Rheumatology & Arthritis Research
revealed that the values of QTc interval increased with the severity
of the capillaroscopic pattern, the differences having statistical
significance (Table 3).
Statistical analysis highlighted the presence of statistically
significant correlations between the values of QTc intervals and
nailfold capillaries density and, on the other hand, with the mean
length of SSc evolution (Table 4).
Table 4: Correlations between QTc values and demographic data.
Correlation Between QTc and Nailfold
r p
Capillaries Density:
Mean age -0.1272 0.57
Mean length of SSc evolution 0.4408 < 0.05
Mean length of Raynaud’s phenomenon
-0.0036 0.98
evolution
Nailfold capillaries density/mm -0.8905 < 0.001
The progression of SSc microangiopathy, proved by nailfold
capillaroscopic pattern, was associated with prolongation of
the QTc interval. If at the beginning of the SSc (revealed by early
capillaroscopic pattern), the correlation between QTc interval and
nailfold capillaries density did not exist, as the disease worsened
(active and late capillaroscopic patterns), the negative correlations
become more and more significant (Table 5). QTc interval [14, 15]. But beside myocardial fibrosis, autonomic
Table 5: Correlations between QTc values and capillaroscopic patterns.
Correlation Between QTc and
r p
Nailfold Capillaries Density/mm:
Early pattern 0.0887 0.69
Active pattern -0.6963 < 0.001
Late pattern -0.8432 < 0.001
Regarding the QTc interval duration according to the SSc-
related antibodies profile, it was found that the presence of RNA-
polymerase III antibodies was associated with the longest duration
of the QTc interval (anti-centromere antibodies: 417.66±37.85
msec, anti-topoisomerase I antibodies: 449.91±40.97 msec, anti-
RNA polymerase III antibodies: 480.71±43.43 msec, p<0.001). But
it should be noted that 4 of the 7 patients with anti-RNA polymerase
III antibodies had late capillaroscopic pattern.
Discussion
The present study performed on patients with SSc, showed
that in these patients, the QTc interval was longer than in
controls. Moreover, there was a negative correlation between
the QTc interval values and the nailfold capillaries density. In
other words, the progression of SSc microangiopathy, proved by
nailfold capillaroscopic pattern, was associated with QTc interval
prolongation. If at the beginning of the SSc (revealed by early
capillaroscopic pattern), this correlation did not exist, as the disease
worsened (active and late capillaroscopic patterns), the correlation
become more and more significant (r = - 0.6963, p<0.001 for the
patients with active capillaroscopic pattern, respective r = - 0.8432,
p<0.001 for the patients with late capillaroscopic pattern).
SSc microangiopathy is present in all organs of these patients.
Nailfold capillaroscopy has become a useful tool in staging of
microcirculation involvement in SSc patients, offering details
about the disease severity and degree of vascularization in
Citation: Alexandru Caraba, Andreea Munteanu, Flavia Corina Babali, Mihaela Nicolin. Corrected QT Interval in Systemic Sclerosis Patients.
Arch Rheum & Arthritis Res. 1(1): 2019. ARAR.MS.ID.000501.
Volume 1-Issue 1
patients with it [10,11]. Cutolo et al. defined three evolution
patterns of microvascular involvement in SSc patients, named
as: early (few giant capillaries, few capillary microhemorrhages,
no evident loss of capillaries, and a relatively well-preserved
capillary distribution), active (frequent giant capillaries, frequent
capillary microhemorrhages, moderate loss of capillaries, absence
of or mildly ramified capillaries with slight disorganization of the
capillary architecture), and late (irregular enlargement of the
capillaries, almost absent giant capillaries and microhemorrhages,
severe loss of capillaries with extensive avascular areas, ramified/
bushy capillaries, and intense disorganization of the normal
capillary array), having a role in assessing the appearance and
progression of sclerodermic microangiopathy [12,13].
Pathogenesis of SSc heart disease is related to cardiac
microangiopathy (without epicardial vessels involvement), which
drives to ischemia, inflammation and fibrosis [3]. Recurrent
myocardial ischemia, induced by microvascular dysfunction
(myocardial Raynaud’s phenomenon), generates patchy myocardial
fibrosis. This myocardial fibrosis is identified in 50% to 70% of
SSc patients, generating prolongation the time required for all
ventricular depolarization and repolarization processes to occur.
The electrocardiographic sign is represented by the prolonged
dysfunction contributes to QTc prolongation, too [6].
Wei et al. showed that the QTc interval prolongation represented
an independent risk factor for cardiac mortality and sudden death
[16]. Arrhythmias may be associated with poor outcome and
represent 6% of the overall causes of death in SSc patients [17].
According to Vacca and el, cardiac arrhythmias are identified in 25-
75% of SSc patients [7].
Prolonged QTc interval was identified in SSc patients even
without clinical signs of miocardial involvement [18].
Studying 72 SSc patients and 64 controls, Morelli et al. showed
that the SSc patients presented significantly longer QTc interval
than the controls (p = 0.0016) [19]. Thirty-eight patients with
SSc (19 patients with dcSSc and 19 with the lcSSc) and 17 healthy
controls were studied by Sgreccia et al. The authors identified that
the SSc patients had increased QTc interval, QT dispersion, and
QTc dispersion [20]. Bellando-Randone et al. identified that the
SSc patients presented prolonged QTc interval, this situation being
associated with increased risk of sudden deaths [21]. In the study
performed by Massie et al., prolonged QTc interval was common
in SSc patients, being associated with anti-RNA polymerase III
antibodies, longer disease duration, and greater disease severity
[22]. In the present study, the patients with anti-RNA polymerase
III antibodies presented the longest duration of QTc interval;
but 57.14% of them had late capillaroscopic pattern. Rosato et
al. studying twenty SSc patients, showed that the values of QTc
intervals were significantly increased in SSc patients than controls
(447msec vs 386msec) (p<0.0001). The authors revealed that the
values of the QT intervals increased with the severity of the nailfold
capillaroscopic pattern: early pattern: 425 msec (421-454), active
pattern 437 msec (416-467), and late pattern 471 msec (445-566)
(p<0.01). No correlations were found between the values of QTc
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 Archives of Rheumatology & Arthritis Research
interval and SSc subset or duration, but the presence of digital ulcers
and high modified Rodnan total skin score were correlated with the
values of this interval [23]. Similar findings regarding to the values
of QTc intervals and nailfold capillaroscopic pattern were identified
in the present study. One study showed that in dcSSc patients, QTc
interval was significantly prolonged than in lcSSc patients [24],
but it has not been confirmed by other studies. Another study
performed on 65 SSc patients and 63 control subjects showed that
the QTc intervals were significantly higher in the former (p < 0.01),
without any difference between patients with dcSSc and lcSSc [15].
QTc interval prolongation in SSc patients with late
capillaroscopic pattern is associated with a high risk of developing
life-threatening ventricular arrhythmias [23]. If the prolonged
QTc interval is demonstrated, then the ambulatory 24-hour ECG
monitoring is required to identify ventricular arrhythmias and
initiate appropriate therapy.
The relatively small number of SSc patients is one of the limits of
this study. Large-scale prospective studies are required to identify
the risk factors of life-threatening ventricular arrhythmias in SSc
patients with prolonged QTc interval.
Conclusion
SSc patients present prolonged QTc interval, even they are
without any cardiac symptoms. In order to identify the SSc heart
disease from its earliest stages, it is advisable to perform the
electrocardiogram once a year, especially in patients with significant
nailfold capillaries findings.
Acknowledgment
None.
Conflict of Interest
The authors declared no conflicts of interest.
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Citation: Alexandru Caraba, Andreea Munteanu, Flavia Corina Babali, Mihaela Nicolin. Corrected QT Interval in Systemic Sclerosis Patients.
Arch Rheum & Arthritis Res. 1(1): 2019. ARAR.MS.ID.000501.
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